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(1) Mitochondrial Diseases

This is the first of a two-part Quest series about mitochondrial myopathy. This article covers the basic biology of mitochondria and explains inheritance patterns and determinants of severity in mitochondrial diseases. Part 2 will discuss diagnosis and treatment, including a look at new information about mitochondrial diseases in the research pipeline.

We all know what it's like to drive or ride in a car that isn't performing at its peak; we know from experience that trouble-shooting the problem can be a difficult, costly proposition.

In some ways, the cells in our bodies are like little mechanical devices that occasionally break down. They have a lot of parts, some moving and some not, each with a specific role to perform in the cell. An endless variety of things can go wrong in the cell, affecting the entire body's ability to perform.

We can compare a cell with muscular dystrophy to a car with cracks in the frame. The cracks become slightly wider whenever the car is driven. In the same vein, a cell with mitochondrial disease might be compared to a car that's only running on three cylinders. No matter how much gas you put into the car, without a fully operating engine it's not going to go over 25 miles per hour.

In each of our cells, the mitochondria (singular: mitochondrion) make up the equivalent of a car's engine. These tiny biological machines combine the food we eat with oxygen to produce energy to keep our bodies going. The energy produced by the mitochondria is stored in the form of a chemical called adenosine triphosphate, or ATP.

In addition to making energy, mitochondria are also deeply involved in a variety of other activities, such as making steroid hormones and manufacturing the building blocks of DNA. Each cell in our body contains, on average, between 500 and 2,000 of these hard-working machines. When the mitochondria aren't functioning properly, an "energy crisis" can develop in tissues such as muscle, brain and heart, which normally are heavy energy consumers.

Just as engine problems can slow or stop a car, problems with mitochondria can bring the body to a halt.

William Duff of Orchard Run, W.Va., who was once an avid hiker, suspected he might have a problem when he started getting tired on the trail and having to take frequent breaks. Then the muscles in his legs began to contract spontaneously all of the time. A mitochondrial disease called MELAS was diagnosed two years ago.

Duff suggests that having MELAS is like experiencing old age at 37.

"Any kind of exertion brings on fatigue. Sometimes I get up in the morning and I just have no energy at all," he says. "It's hard to explain. Just simple daily functions are very tiring."

The Downs Family

Duff's spontaneous muscle contractions have spread throughout his extremities, trunk and face. Now he's also having trouble with drooping eyelids, memory deficits, stomach reflux, and difficulty absorbing nutrients.

For Lori and Jeff Downs of North Reading, Mass., their daughter Alycia's mitochondrial disease has meant an uphill battle to cope with her severe gastrointestinal problems.

"Alycia was a normal-term baby and her birth was fairly normal," says Lori Downs. "The first problem that we had was with her feeding -- it was just a struggle. It would take her an hour to take that half an ounce and she would sweat and struggle, and she wasn't gaining weight."

The Downses eventually worked out a feeding solution for Alycia by boosting her calorie intake and making the nipple easier to use. Now almost 4 years old, Alycia still struggles with gaining weight, and has some muscle weakness, drooping eyelids, difficulty maintaining her balance and focused cognitive deficits.

The experiences of Duff and the Downs family illustrate just a few of the different manifestations of mitochondrial disease. In the same way that a car can show many different signs of engine problems, mitochondrial diseases -- of which hundreds of varieties have been identified -- can cause a complex variety of symptoms.

These include muscle weakness, muscle cramps, seizures, food reflux, learning disabilities, deafness, short stature, paralysis of eye muscles, diabetes, cardiac problems and strokelike episodes, to name a few. The symptoms can range in severity from life-threatening to almost unnoticeable, sometimes taking both extremes in members of the same family.

Because some people have specific subsets of these symptoms, clinical researchers have grouped those that occur together into "syndromes," producing a bewildering array of descriptive acronyms such as MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes) or MERFF (myoclonus epilepsy with ragged red fibers).

You may also hear the terms "mitochondrial myopathy" (indicating muscle involvement) or "mitochondrial encephalomyopathy" (indicating brain and muscle involvement). MDA covers diseases in both of these categories, which include many different syndromes (see mitochondrial encephalomyopathies chart, below).

The mitochondrial encephalomyopathies and myopathies are typically caused by defects in a part of the mitochondrion known as the respiratory chain or the electron transport chain. To see exactly how these diseases occur, see "What Mitochondria Do and What Can Go Wrong."

COMMON MITOCHONDRIAL DISEASES AFFECTING MUSCLE

The terminology used in describing mitochondrial disorders can be confusing. A single syndrome (combination of symptoms) may have many different causes, while more than one syndrome may have the same cause.

In most cases, the underlying causes of these syndromes are deficiencies in the respiratory chain of the mitochondria (see "What Mitochondria Do"). You may be given a diagnosis named for the cause, such as COX deficiency or complex I and IV deficiency. The following have names based on the symptoms of the disease, but are caused by respiratory chain deficiencies.

NARP: Neuropathy, ataxia and retinitis pigmentosaOnset: Infancy or childhoodDisease characteristics: May cause vision problems, lack of coordination and mental retardation. This syndrome may represent a less severe form of MILS.

Pearson syndrome:Onset: ChildhoodDisease characteristics: Severe anemia and pancreas malfunction; children who survive the disease may develop KSS as adolescents.

WHAT MITOCHONDRIA DO, AND WHAT CAN GO WRONG

When the breakdown products of the food that we eat enter the mitochondria for processing, they're passed along a well-orchestrated assembly line made up of hundreds of proteins, each with a specific role to play in the energy production process. Raw materials enter the beginning of the assembly line, and ATP energy molecules come out the other side.

The major steps in the energy extraction process are (see the following illustration):

import and export of materials, such as fat and sugar derivatives, to and from the mitochondria

the breakdown of fatty acids through beta-oxidation and the removal of electrons in the citric acid cycle

the passage of electrons through the major complexes of the respiratory chain, or electron transport chain, and

the manufacture of ATP by ATP synthase.

When any one of these steps is blocked, usually because a genetic defect has prevented the manufacture of a protein required for that step, mitochondrial disease can occur. The body can't function properly because the cell's ability to make energy is reduced or stopped, and metabolic intermediates and toxic by-products begin to build up.

The energy shortage in the tissues is the major cause of muscle weakness, fatigue and problems in the heart, kidneys, eyes and endocrine system. The buildup of toxic intermediates can be responsible for liver problems, muscle cramps, brain dysfunction or even greater mitochondrial damage. Many times these two types of problems reinforce one another, each making the other worse. (The specific problems and symptoms that occur in mitochondrial disorders, and their management, will be discussed in greater detail in Part 2 of this series.)

Salvatore DiMauro, a neurologist at Columbia University in New York, says that, although there are many different types of defects that cause mitochondrial disorders, the term mitochondrial encephalomyopathy has come to refer only to disorders of the respiratory chain (numbers 3 and 4 in the illustration). (The respiratory chain is part of the cell and has nothing to do with a person's breathing.)

The respiratory chain consists of four large protein complexes: I, II, III and IV (cytochrome c oxidase, or COX), ATP synthase, and two small molecules that ferry around electrons, coenzyme Q10 and cytochrome c. The respiratory chain is the final step in the energy-making process in the mitochondrion where most of the ATP is generated; as DiMauro puts it, it's "the business end of mitochondrial metabolism." Mitochondrial encephalomyopathies that can be caused by deficiencies in one or more of the specific respiratory chain complexes include MELAS, MERFF, Leigh's syndrome, KSS, Pearson, PEO, NARP, MILS and MNGIE.

(2) Treatment of Mitochondrial Diseases

Each of our cells contains, on average, 500 to 2,000 little "factories" called mitochondria that are responsible for supplying our energy needs. When the mitochondria aren't working properly, the effects are particularly apparent in parts of the body with high energy requirements, such as the nervous system, skeletal muscles and heart.

This is the second article in a two-part series on mitochondrial diseases affecting these organs. Part 1 (vol. 6, no. 4) covered mitochondrial anatomy, the basics of mitochondrial disease inheritance and common types of mitochondrial disorders affecting muscle.

Part 2 takes a closer look at diagnosis, symptoms and their management. In addition, MDA researcher and mitochondria expert Eric Schon of Columbia University gives an inside view of projects in the research pipeline that hold promise for mitochondrial disease treatments.

Mitochondrial disorders differ from other genetic disorders affecting the muscles in a number of ways. Most significantly, although mitochondrial disease can present as a "pure myopathy," meaning that only the skeletal or heart muscles are affected, it more often causes problems in many different organ systems, including the nervous, visual, renal (kidneys), digestive and circulatory systems.

The mitochondria are essential for turning the food we eat into energy in the form of the molecule ATP. Although there are many working parts in each mitochondrion, the mitochondrial encephalomyopathies (those disorders affecting brain and muscle and the type covered in MDA's program) are most often caused by defects in the proteins that make up the respiratory chain. The respiratory chain inside the mitochondrion is an assembly line of protein complexes that combines electrons with oxygen to generate potential energy in the form of ATP. (This respiratory chain has nothing to do with breathing.)

BEYOND MUSCLE WEAKNESS

Despite the fact that mitochondrial diseases can be so variable and affect so many organ systems, a few symptoms are common to many of these disorders. These include muscle weakness, muscle cramps, extreme fatigue, gastrointestinal problems (constipation, acid reflux), droopy eyelids (ptosis), eye muscle paralysis (external ophthalmoplegia), retinal degeneration (retinitis pigmentosa) with visual loss, seizures, ataxia (loss of balance and coordination) and learning delays. See illustration below:

Commonly Affected Systems in Mitochondrial Disorders

The main problems associated with mitochondrial disease -- low energy, free radical production and lactic acidosis -- can result in a variety of symptoms in many different organs of the body. This diagram depicts common symptoms of mitochondrial disease, of which most people have a specific subset. Many of these symptoms are very treatable.

Another category of symptoms called "soft signs" may be noticeable in people who have none of the more overt symptoms of mitochondrial disease. Soft signs include deafness, mild exercise intolerance, diabetes, short stature and migrainous headaches.

Sometimes when a person is found to have a mitochondrial disease on the basis of more severe symptoms, the soft signs of the disease may be recognized in hindsight in other family members.

All of these problems start when something goes wrong in the mitochondria. Some are a direct result of interruptions in the energy supply, while others may be due to the secondary buildup of toxic byproducts, and still others to combinations of these two problems.

When key components of the respiratory chain in the mitochondria are missing or defective, the result is kind of like the aftermath of a train derailment. First, because a component of the assembly line isn't working, electrons aren't delivered. ATP isn't made efficiently and the cells lack the energy to perform their normal functions.

Second, all of the steps behind the point where the problem starts become backed up -- often leading to abnormal chemistry that produces toxic charged molecules. These byproducts include free radicals and excess metabolites, such as lactic acid, that can be harmful in large quantities.

These observations lead to three prime suspects as causes of the symptoms of mitochondrial disease: energy deficit, free radical generation and the buildup of toxic metabolites. Researchers are looking for ways to address these underlying causes. In the meantime, it's good to keep in mind that, although mitochondrial diseases are rare, many of their specific symptoms, such as heart failure and seizures, are relatively common in the general population. Thus, good medical treatments exist to help manage these symptoms.

ENERGY LOSS AND DIET

Tissues that need large amounts of energy, such as the brain, heart, skeletal muscles, eye muscles and the renal tubules of the kidney, probably malfunction, in part, because they run out of fuel. The result is muscle weakness, cardiomyopathy, renal problems, droopy eyelids, cognitive problems and general fatigu

Although there's no way to combat this type of energy loss directly, eating a healthy, well-balanced diet is important. Sometimes special diets are necessary or beneficial in the management of specific mitochondrial and metabolic diseases. Always consult your doctor on this point, as dietary changes can be dangerous in some of these disorders.

Also, a preliminary report indicates that the dietary supplement creatine may produce modest increases in muscle strength in people with a variety of neuromuscular disorders, including mitochondrial diseases.

Creatine is a small molecule similar to an amino acid that's converted to a compound called phosphocreatine in the body and used as a source of energy. Phosphocreatine actually contains even more energy than ATP and is normally used by our muscle cells for supplying the first burst of energy at the start of strenuous physical activity.

But keep in mind that the experimental results with creatine are very preliminary, and the long-term effects of creatine supplementation in people with any kind of neuromuscular disorder aren't yet known.

Also, although dietary supplements are available over the counter without a prescription, that doesn't mean they're always harmless. You should consult your physician before taking any dietary supplement.

FREE RADICALS AND ANTIOXIDANTS

Free radicals are highly reactive charged molecules that can damage DNA and cell membranes by oxidizing them (the same chemical process that causes iron to rust). Normally, the mitochondrial respiratory chain generates a low level of free radicals during the process of making ATP. When there's a malfunction in the respiratory chain, the scale may be tipped toward higher free radical production.

These free radicals, in turn, may cause further damage to the mtDNA (the unique DNA that's found only inside the mitochondria), creating a vicious cycle of damage and free radical production. It's unclear exactly how large a role the generation of free radicals plays in causing or worsening the symptoms of mitochondrial disease, but to play it safe, many doctors recommend antioxidants to their patients.

Antioxidants, usually in the form of vitamins or cofactors, help neutralize free radicals. These same antioxidants and vitamins may also help the struggling enzymes of the respiratory chain run more smoothly. Unfortunately, studies of their effects in people with mitochondrial diseases have produced mixed results, usually because some of the trial participants respond to the supplements and others don't.

"It probably won't hurt, but it probably won't do much good," says one researcher of taking antioxidants. "It's a bit like emptying the ocean with a teaspoon."

Some examples of antioxidants are vitamin E, coenzyme Q10, idebenone (related to coQ10, but penetrates the nervous system more easily), lipoic acid, vitamin C, vitamin K and riboflavin (B2). Many doctors prescribe a "cocktail" of these supplements tailored to the individual patient.

TOXIC METABOLITE BUILDUP AND CARNITINE

When the mitochondrial respiratory chain is blocked, metabolites that are normally processed by its enzymes may build up in the cells and cause problems.

For example, pyruvate is a chemical derived from glucose that's normally shipped into the mitochondria and then processed further so that its potential energy can be harvested by the respiratory chain.

However, when the respiratory chain is blocked, pyruvate accumulates outside the mitochondria, and when too much pyruvate has accumulated, the cells start to convert it to lactic acid.

"Many patients with mitochondrial disease have lactic acidosis -- lactate in the blood," neuroscientist Eric Schon of Columbia University in New York says. "And there's decent evidence that the lactate isn't just a sign of faulty mitochondria, but that the lactate itself is bad -- especially in the brain, but probably also in the muscle. If this is true, then holding that lactate down would help the patient."

With this in mind, two groups, one at the University of Florida led by Peter Stacpoole and one at the University of California-San Diego led by Richard Haas, are conducting clinical trials with a drug called dichloroacetate (DCA) to try to lower lactate levels in children with Leigh syndrome, Pearson syndrome, MELAS or MERFF (all mitochondrial myopathies).

A third group of researchers led by Darryl DeVivo of Columbia University is also planning to start a DCA trial next spring, but it will limit the enrollment to people with MELAS who have the A3243G mutation. DeVivo says lactate levels in the brain are higher in MELAS than in other mitochondrial diseases, and he hopes that, by narrowing the participation criteria, the study will produce more meaningful results on the effects of DCA.

In addition to lactic acid, other metabolites that normally feed into the respiratory chain can build up in the cells of people with mitochondrial diseases.

In an attempt to rid the body of certain of these extra metabolites, carnitine supplementation is sometimes tried. Carnitine is a natural compound made in the body that functions as a "molecular escort" for other molecules.

One of the duties of carnitine is to move long-chain fatty acids into the mitochondria. Another of its important roles is to bind to extra metabolites and escort them out of the cells and into the kidneys for excretion in the urine.

In this way, carnitine helps the body rid itself of certain extra metabolites.

Carnitine supplementation is often prescribed in mitochondrial disorders, but, as with antioxidants, the evidence that it's helpful is controversial. Carnitine can be bought over the counter at health food stores or can be taken in the prescription form Carnitor (the maker of Carnitor, Sigma Tau, guarantees the purity of its product). Again, consult your doctor before taking any kind of drug or supplement.

Although it may not be possible to treat all of the primary causes of mitochondrial diseases, a recent study in the journal Neurology suggests that people with diseases such as MELAS, MERFF and progressive external ophthalmoplegia (PEO) are actually in greater danger from the treatable complications such as heart failure or stroke than from the mitochondrial disease itself. The authors advise that people living with a mitochondrial disease could benefit by more actively monitoring these conditions and seeking prompt medical attention when necessary.

Fortunately, good treatments do exist for many of the associated complications of mitochondrial disease. For instance, seizures can be managed with antiepileptic medications such as carbamazepine. However, the common antiepileptic valproic acid should be avoided because it depletes the body of carnitine.

Heart failure or arrhythmias can be managed with medications or pacemakers.

Also, people at risk for stroke can reduce that risk with medication, and diabetes can often be managed through careful diet and medication. Specialists treating these symptoms should always be informed about your mitochondrial disorder.